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MicroRNA 17-92 cluster mediates ETS1 and ETS2-dependent RAS-oncogenic transformation

Mohamed Kabbout1, Duaa Dakhlallah2, Sudarshana Sharma3

  • 1Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America; Graduate Program in Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, Ohio, United States of America; Solid Tumor Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.

Plos One
|June 27, 2014
PubMed

Insights

Transcription factors Ets1 and Ets2 are crucial for Ras-induced cell transformation. Deleting both Ets1 and Ets2 inhibits transformation by blocking MYC and microRNA 17-92 expression, key drivers of this process.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • ETS-family transcription factors (Ets1, Ets2) are downstream effectors of the RAS/ERK pathway.
  • Their precise role in Ras-mediated cellular transformation remains incompletely understood.

Purpose of the Study:

  • To elucidate the function of Ets1 and Ets2 in Ras-induced cellular transformation.
  • To investigate the molecular mechanisms by which Ets1/Ets2 influence transformation, focusing on MYC and microRNA 17-92.

Main Methods:

  • Generation of Ets1/Ets2 double knockout mouse embryonic fibroblasts.
  • Analysis of HrasG12V-induced transformation in vitro and in vivo.
  • Assessment of gene and microRNA expression levels (MYC, microRNA 17-92) and transcription factor binding.

Main Results:

  • Deletion of both Ets1 and Ets2 significantly inhibited HrasG12V-induced transformation.
  • HrasG12V expression upregulated ETS1, ETS2, and MYC, and increased microRNA 17-92 cluster expression.
  • Ets1/Ets2 and MYC collaborated to drive microRNA 17-92 expression in transformed cells.

Conclusions:

  • Ets1 and Ets2 are essential for HrasG12V-induced cellular transformation.
  • The pathway involves Ets1/Ets2-mediated upregulation of MYC and the microRNA 17-92 cluster.
  • MYC and microRNA 17-92 are direct downstream effectors of Ets1/Ets2 in Ras transformation.

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